The Androgen Axis in Recurrent Prostate Cancer

Abstract

Purpose. Prostate cancer that recurs during androgen deprivation therapy is referred to as androgen-independent. High levels of expression of androgen receptor and androgen receptor-regulated genes in recurrent prostate cancer suggest a role for androgen receptor and its ligands in prostate cancer recurrence.Experimental Design. Recurrent prostate cancer specimens from 22 men whose prostate cancer recurred locally during androgen deprivation therapy and benign prostate specimens from 48 men who had received no prior treatment were studied. Androgen receptor expression was measured using monoclonal antibody and automated digital video image analysis. Tissue androgens were measured using radioimmunoassay.Results. Epithelial nuclei androgen receptor immunostaining in recurrent prostate cancer (mean optical density, 0.284 ؎ SD 0.115 and percentage positive nuclei, 83.7 ؎ 11.6) was similar to benign prostate (mean optical density, 0.315 ؎ 0.044 and percentage positive nuclei, 77.3 ؎ 13.0). Tissue levels of testosterone were similar in recurrent prostate cancer (2.78 ؎ 2.34 pmol/g tissue) and benign prostate (3.26 ؎ 2.66 pmol/g tissue). Tissue levels of dihydrotestosterone, dehydroepiandrosterone, and androstenedione were lower (Wilcoxon, P ‫؍‬ 0.0000068, 0.00093, and 0.0089, respectively) in recurrent prostate cancer than in benign prostate, and mean dihydrotestosterone levels, although reduced, remained 1.45 nM. Androgen receptor activation in recurrent prostate cancer was suggested by the androgenregulated gene product, prostate-specific antigen, at 8.80 ؎ 10.80 nmol/g tissue.Conclusions. Testosterone and dihydrotestosterone occur in recurrent prostate cancer tissue at levels sufficient to activate androgen receptor. Novel therapies for recurrent prostate cancer should target androgen receptor directly and prevent the formation of androgens within prostate cancer tissue.

Fibroblasts prolong serum prostate-specific antigen decline after androgen deprivation therapy in prostate cancer

“…DHT concentrations in the incubation medium were chosen based on previous studies of tissue DHT levels in recurrent PCa. 23,24 Growth Factor and Cytokine Stimulation of Cell Growth Examination of the effects of growth factor and cytokine stimulation was performed as previously described, 17 with minor modifications. LNCaP cells were cultured in phenol red (+) RPMI-1640 supplemented with 10% FBS for 2 days, and the culture medium was then replaced with phenol red ( − ) RPMI-1640 supplemented with 0.5% CS-FBS containing DHT (0.1 nM).…”

Androgen receptor CAG repeat length contraction in diseased and non-diseased prostatic tissues

“…While a linear relationship between immunohistochemical staining of AR and AR expression has been established, 25,26 a visual scoring of AR cannot accurately reflect the often-subtle variation in immunohistochemical-staining intensity. 27 Therefore, computerassisted image analysis, similar to that used by other investigators to measure AR immunostaining 21,25,27,28 was used to quantify AR expression. This confirmed the variability in intensity of AR immunohistochemical staining as shown by scatter plots (Figure 7).…”

CUA-CUOG Guidelines for the Management of Castration Resistant Prostate Cancer (CRPC): 2013 Update

“…Most recently, the terms castration-resistant prostate cancer or castration-recurrent prostate cancer were introduced with the realization that extra testicular androgen production plays a significant role in the resistance of prostate cancer cells to medical or surgical castration therapy. 1 In their second publication, the Prostate Cancer Working Group defined CRPC as a continuum on the basis of whether metastases are detectable (clinically or by imaging) and whether the serum testosterone is in the castrate range by Castration-resistant prostate cancer (CRPC) is defined by disease progression despite androgen depletion therapy (ADT) and may present as either a continuous rise in serum prostatespecific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases. 3 Prognosis is associated with several factors, including performance status, presence of bone pain, extent of disease on bone scan, and serum lactate dehydrogenase and alkaline phosphatase levels.…”